Lupin Exh. 1023
`
`

`
`PRODUCT INFORMATION
`
`It is not known whether this drug is se-
`Nursing Mothers:
`creted in human milk and because of the potential for seri-
`ous adverse reactions from folodipine in the infant, a deci-
`sion should be made whether to discontinue nursing or to
`discontinue the drug, taking into account the importance of
`the drug to the mother.
`Pediatric Use: Safety and effectiveness in pediatric pa-
`tients have not been established
`
`’ Based on patient weight of 50 kg
`ADVERSE REACTIONS
`
`In controlled studies in the United States and overseas, ap-
`proximately 3000 patients were treated with felodipine as
`either the extended-release or the immediate-release formu-
`lation.
`The most common clinical adverse events reported with
`PLENDIL administered as monotherapy at the recom-
`mended dosage range of 2.5 mg to 10 mg once a day were
`peripheral edema and headache. Peripheral edema was
`generally mild, but it was age and dose related and resulted
`in discontinuation of therapy in about 3% of the enrolled
`patients. Discontinuation of therapy due to any clinical ad-
`verse event occurred in about 6% of the patients receiving
`PLENDIL, principally for peiipheral edema, headache, or
`flushing
`Adverse events that occurred with an incidence of 1 5% or
`greater at any of the recommended doses of 2.5 mg to 10 mg
`once a day (PLENDIL, N = 861; Placebo, N = 334), without
`i~cgai'(l to causality, are compared to placebo and are listed
`by dose in the table below These events are reported from
`controlled clinical trials with patients who were randomized
`to a fixed dose of PLENDIL or titrated from an initial dose
`of2 5 mg or 5 mg once a day A dose of 20 mg once a day has
`been evaluated in some clinical studies Although the anti-
`liypeitensive effect of PLENDIL is increased at 20 mg once
`a day, there is a dispropoitionate increase in adverse events,
`especially those associated with vasodilatory effects (see
`DOSAGE and ADMINISTRATION),
`[See table at bottom of previous page]
`Adverse events that occurred in 0 5 up to 1.5% of patients
`who received PLENDIL in all controlled clinical trials at the
`recommended dosage range of 2 5 mg to 10 mg once a day,
`and serious adverse events that occurred at a lower rate, or
`events reported during marketing experience (these lower
`rate events are in italics) are listed below These events are
`listed in order of decreasing severity within each category,
`and the relationship of these events to administration of
`PLENDIL is uncertain Body as .3 Whole: Chest pain, facial
`edema, flu—like illness; Cardiovascular: Myocardial infarc-
`lion,
`liypotensioii, syncope, angina pcctoris, airliyfhiniri,
`tachycardia, premature beats; Digestive:/Sbdoniinal pain,
`diarrhea, vomiting, dry mouth, flatulence, acid regurgita-
`tion; Endocrine: Gyiiecomastia; Hematologic:Anemia, Met-
`abolic: ALT (SGPT) increased; Musculoskeletal: Arthralgia,
`back pain, leg pain, foot pain, muscle cramps, myalgia, arm
`pain, knee pain, hip pain, Nervous/Psychiatric: Insomnia,
`depression, anxiety disorders, irritability, nervousness,
`somnolence, decreased libido; Respiratory: Dyspnea, phar-
`yngitis, bronchitis, influenza, sinusitis, epistaxis, respira-
`tory infection; Skin: Contusion, erythema, urticaria; Special
`Senses: Visual disturbances; Urogenital: Impotence, uri-
`nary frequency, urinary uigency, dysuria, polyuria.
`Gmgival Hyperplasia——Gingival hyperplasia, usually mild,
`occuiied in <05% of patients in controlled studies. This
`condition may be avoided or may regress with improved
`dental hygiene. (See PRECAUTIONS, Information for Pa-
`tients.)
`Clinical Laboratory Test Findings: Serum Elcctrolytcs—No
`significant eflects on serum electrolytes were obseived dur-
`ing short- and long-term therapy (see CLINICAL PHARMA-
`COLOGY, Renal/Endociine Effects)
`Scrum Glucosc——No significant effects on fasting serum glu-
`cose were observed iii patients treated with PLENDIL in
`the U.S. controlled study
`Liver E'izzymes—1 of 2 episodes of elevated serum trans-
`aniinases decreased once drug was discontinued in clinical
`studies; no follow-up was available for the other patient.
`OVERDOSAGE
`
`Oral doses of 240 iiig/kg and 264 mg/kg in male and female
`mice, respectively, and 2390 mg/kg and 2250 mg/kg in male
`and female rats, respectively, caused significant lethality
`In a suicide attempt, one patient took 150 mg felodipine to-
`gether with 15 tablets each of atenolol and spironolactone
`and 20 tablets of nitrazepam. The patient’s blood pressure
`and heart rate were normal on admission to hospital; he
`subsequently recovered without significant sequclae.
`Overdosage might be expected to cause excessive peripheral
`vasodilation with marked hypotcnsion and possibly brady-
`cardia
`If severe hypotension occui's, symptomatic tieatment should
`be instituted The patient should be placed supine with the
`legs elevated. The adiiiinistration of intravenous fluids may
`be useful to treat hypotension due to overdosage with cal-
`cium antagonists In case of accompanying bradycardia, at-
`iopine (0.5—1 mg) should be administered intravenoiisly.
`Sympathoniimetic diugs may also be given if the physician
`feels they are warranted.
`It has not been established whether fclodipine can be re-
`moved from the ciiculation by liemodialysis.
`To obtain up-to-date information about the treatment of
`overdose, consult your Regional Poison-Control Centei.
`
`Telephone numbers of certified poison—control centers are
`listed in gie Pliysicians’Dcsk Re/‘eiencc (FDR) In managing
`overdose, consider the possibilities of multiple-drug over-
`doses, drug-drug interactions, and unusual ding kinetics in
`your patient.
`DOSAGE AND ADMINISTRATION
`
`The recommended starting dose is 5 mg once a day. Depend-
`ing on the patient’s iesponse, the dosage can be decreased to
`2 5 mg or increased to 10 mg once a day. These adjustments
`should occur generally at intervals of not less than 2 weeks.
`The recoiiimeiided dosage range is 25-10 mg once daily. In
`clinical trials, doses above 10 mg daily showed an increased
`blood pressure response but a large increase in the rate of
`peiipheral edema and other vasodilatoiy adverse events
`(see ADVERSE REACTIONS). Modification of the recom-
`mended dosage is usually not required in patients with re-
`nal impairment.
`,
`PLENDIL should regularly be taken either without food or
`with a light meal (see CLINICAL PHARMACOLOGY, Phar-
`macokinetics and Metabolism). PLENDIL should be swal-
`lowed whole and not crushed or chewed.
`Use in the Elderly oi Parieiits with Impaired Liver Func-
`tioiz-—Patients over 65 years of age, or patients with im-
`paired liver function, may develop higher plasma concentra-
`tions of felodipine; therefore, a starting dose of 2 5 mg once
`a day is iecomniended. Dosage may be adjusted as described
`above. (See PRECAUTIONS )
`
`HOW SUPPLIED
`
`No 3584- Tablets PLENDIL, 2 5 mg, aie sage green, round
`convex tablets, with code 450 on one side and PLENDIL on
`the other They are supplied as follows:
`NDC 0186-0450-28 unit dose packages of 100
`NDC 0186-0450-58 imit of use bottles of 100
`NDC 0186-0450-31 unit of use bottles of 30
`No. 3585-—-Tablets PLENDIL, 5 mg, are light red-brown,
`round convex tablets, with code 451 on one side and
`PLENDIL on the other, They are supplied as follows:
`NDC 0186-0451-28 unit dose packages of 100
`NDC 0186-0451-58 unit of use bottles of 100
`NDC 0186-0451-31 unit of use bottles of 30
`No 3586—Tablets PLENDIL, 10 mg, are red-brown, round
`convex tablets, with code 452 on one side and PLENDIL on
`the other They are supplied as follows:
`NDC 0186-0452-28 unit dose packages of 100
`NDC 0186-0452-58 unit of use bottles of 100
`NDC 0186-0452-31 unit of use bottles of 30
`Storage
`i
`Store below 30°C (86"F). Keep container tightly closed Pro-
`tect from light
`m""” '
`‘
`'
`Manufactured by.
`J
`Merck & Co., Inc , West Point, PA 19486
`Distributed by:
`Astra Pharmaceuticals, L P, Wayne, PA 19087
`63000211
`Issued December 1998
`Shawn NI. Product Identification Guide, page 305
`
`POLOCAINE®
`[pd ’-I6-caine "l
`(Mepivacaine Hydrochloride Injection, USP)
`POLOCA|NE®-MPF
`(Meplvacaine Hydrochloride Injection, USP)
`THESE SOLUTIONS ARE NOT INTENDED FOR SPINAL
`ANESTHESIA OR DENTAL USE A
`
`Bi
`
`(For details of indications, dosage and administration, pre-
`cautions, and adverse reactions, see circular in package.)
`HOW SUPPLIED
`POLOCAINE-MPF (Mepivacaine HCI Injection, USP) with-
`out preseivatives is available as follows:
`1% Single-dose vials of 30 mL (NDC 0186-0412-01)
`1.5% Single-dose vials of 30 mL (NDC 0186-0418-01)
`2% Single-dose vials of 20 iiiL (NDC 0186-0422-01)
`POLOCAINE (Mepivacaine HCI Injection,,USP) with pre-
`servatives is available as follows
`1% Multiple-dose vials of 50 mL (NDC 0186-0410-01)
`2% Multiple-dose vials of 50 iiiL (NDC 0186-0420-01)
`Unused portions of solutions not containing preservatives
`should be discarded.
`Store at controlled room temperatuie 15°— 30°C (59°~86°F).
`0216G8RO0
`Iss 1/92
`
`PRILOSEC®
`(omeprazole)
`DELAVED-RELEASE CAPSULES
`
`I}
`
`DESCRIPTION
`The active ingredient in PRILOSEC‘ (oinopiazole) Delayed-
`Release Capsules is a substituted beiiziiiiidazole, 5-meth-
`oxy-2-fl(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfi-
`iiyl]-1H-beiiziinidazole, a compound that inhibits gastric
`acid secretion. Its empirical foimiila is C,7H,9N;,O3S, with a
`molecular weight of345,/12. The striictural formula is:
`[See chemical structure at top of next column]
`Omeprazole is a white to off-white crystalline powder which
`melts with decomposition at about 155°C It is a weak base,
`freely soluble in ethanol and methanol, and slightly soluble
`
`ASTRAZE NECA LP/617
`
`0
`Hll _f.CH
`Q1? W N‘
`A
`H3C
`/ ca,
`OCH;
`
`HJCO
`
`in acetone and isopropanol and veiy slightly soluble in wa-
`ter. The stability of oineprazole is a function of pH; it is rap-
`idly degraded in acid media, but has acceptable stability un-
`der alkaline conditions.
`PRILOSEC is supplied as delayed-release capsules for oral
`administration. Each delayed-release capsule contains ei-
`ther 10 mg, 20 mg or 40 mg of omeprazole in the form of
`enteiic-coated granules with the following inactive ingredi-
`ents: cellulose, disodium hydrogen phosphate, hydroxypro-
`pyl cellulose, hydroxypropyl niethylcellulose, lactose, man-
`nitol, sodium lauryl sulfate and other ingredients. The cap‘-
`sule shells have the following inactive ingredients: gelatin-
`NF, FD&C Blue #1, FD&C Red #40, D&C Red #28, titanium
`dioxide, synthetic black iron oxide, isopropanol, butyl alco-
`hol, I"D&C Blue #2, D&C Red #7 Calcium Lake, and, in ad-
`dition, the 10 mg and 40 mg capsule shells also contain
`D&C Yellow #10
`
`‘Registered trademark of Astra AB
`©Asti'a Pharmaceuticals, LB, 1998
`All rights reseiyed
`CLINICAL PHARMACOLOGY
`Pharmacokinetics and Metabolism: Omeprazole
`PRILOSEC Delayed-Release Capsules contain an enteric-
`coated granule formulation of onieprazole (because omepra-
`zole is acid-labile), so that absorption of omeprazole begins
`only after the granules leave the stomach. Absorption is
`rapid, with peak plasma levels of omeprazole occurring
`within 0.5 to 3.5 hours. Peak plasma concentrations ofome-
`prazole and AUC are approximately propoitional to doses
`up to 40 mg, but because of a saturable first-pass effect, a
`gieater than liiieai' response in peak plasma concentration
`and AUC occurs with doses greater than 40 mg. Absolute
`bioavailability (compared to intravenous administration) is
`about 30-40% at doses of 20-40 mg, due in large part to
`presystemic metabolism In healthy subjects the plasma
`half-life is 0 5 to 1 hour, and the total body clearance is 500-
`600 mL/min. Protein binding is approximately 95%.
`The bioavailability ofomeprazole increases slightly upon re-
`peated administration of PRILOSEC Delayed-Release Cap-
`sules
`Following single dose oral administration of a buffered so-
`lution of omeprazole, little if any unchanged drug was ex-
`creted in urine. The majority of the dose (about 77%) was
`eliminated in urine as at least six metabolites. ’I‘wo were
`identified as hydroxyomeprazole and the corresponding car-
`boxylic acid The remainder of the dose was recoverable in
`feces This implies a significant biliary excretion of the me-
`tabolites of omeprazole Three metabolites have been iden-
`tified in plasma~the sulfide and sulfone derivatives of ome-
`prazole, and hydroxyomeprazole. These metabolites have
`very little or no antisecretory activity.
`In patients with chronic hepatic disease, the bioavailability
`increased to approximately 100% compared to an IV. dose,
`reflecting decreased first-pass effect, and the plasma half-
`life of the drug increased to nearly 3 hours compared to the
`half-life in normals of 0 5-1 hour. Plasma clearance aver-
`aged 70 mL/min, compared to a value of 500-600 mL/min in
`normal subjects.
`In patients with chronic renal impairment, whose creati-
`nine clearance ranged between 10 and 62 mL/min/1 73 1112,
`the disposition of omeprazole was veiy similar to that in
`healthy volunteers, although there was a slight increase in
`bioavailability. Because urinary excretion is a primary route
`of excretion of omeprazole metabolites, their elimination
`slowed in proportion to the decreased creatinine clearance
`The elimination rate of omeprazole was somewhat de-
`creased in the elderly, and bioavailability was increased
`Omeprazole was 76% bioavailable when a single 40 mg oral
`dose of omeprazole (buffered solution) was administered to
`healthy elderly volunteers, versus 58% in young volunteers
`given the same dose Nearly 70% of the dose was recovered
`in urine as metabolites of oiiieprazole and no unchanged
`drug was detected. The plasma clearance of omeprazole was
`250 mL/min (about half that of young volunteers) and its
`plasma half-life averaged one hour, about twice that of
`young healthy volunteers
`In pharmacokinetic studies of single 20 mg omepiazole
`doses, an increase in AUC of approximately four-fold was
`noted in Asian subjects compared to Caucasians.
`Dose adjustment, particularly where maiiitenaiice of heal-
`ing of erosive esophagitis is indicated, for the hepatically
`iinpaiied and Asian subjects should be considered.
`Pharmacokinefics: Combination Therapy with Antimicrobi-
`als
`Omeprazole 40 mg daily was given in combination with
`claritliromycin 500 mg every 8 hours to healthy adult male
`subjects The steady state plasma concentrations of omepra-
`zole were increased (Cum, AUC0_2,, and TV, increases of
`30%, 89% and 34% respectively) by the concomitant admin-
`istration of claritliromycin. The obseived increases in ome-
`prazole plasma concentration were associated with the fol-
`lowing pharmacological effects The mean 24-hour gastric
`pH value was 5 2 when omeprazolc was administered alone
`and 5.7 when co-administered with clarithromycin.
`'I‘he plasma levels of clarithromycin and l4-hydroxy-
`clarithromycin were increased by the concomitant adminis-
`tration of omeprazole For clarithromycin, the mean C,,,,,,
`was 10% greater, the mean C,,,,,, was 27% greater, and the
`
`Continued on next page
`...u nnnn nnnw ........i......... ._4 x .
`.
`. a-.-. 1. i-,
`
`0.
`
`
`
`

`
`618/ASTRAZENECA LP
`
`PHYSICIANS’ DESK REFERENCE®
`
`Pri|osec—Cont.
`_-_,g
`
`Per-Protocol and Intent-to-Treat H. pylori Eradication Rates
`% of Patients Cured [95% Confidence Interval]
`
`7 PKILOSEC +claritliromycin +amoxicillin
`Clarithromycin +amoxicillir.
`
`“ii-..€
`;
`
`
`"f
`,
`,
`'é "
`(Ii = 64)
`— 6%)
`--
`*78 l67, 80]
`"73 [61, 82]
`41 [29, 54]
`36 [26, 47]
`(n = 65)
`(ii = 77)
`(ii = 68)
`(n = 83)
`’90 [80, 96]
`"*83 [74, 91]
`33 l24, 44]
`32 [23, 421
`(n = 69)
`(ti = 84)
`(n = 93)
`(n = 99)
`{Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer, studies 126 and 127;
`history of ulcer within 5 years, study M96-446) and H. pylon infection at baseline defined as at least two of three positive
`endoscopic tests from CLOtest®, histology, and/or culture Patients were included in the analysis if they completed the
`study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were
`included in the analysis as failures of therapy. The impact of eradication on ulcer recurrence has not been assessed in
`patients with a past history of ulcer.
`-
`iPatients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal
`ulcer disease. All dropouts were included as failures of therapy
`‘(p<0_05) versus clarithroinycin plus amoxicilliii.
`
`H pylori Eradication Rates (Per-Protocol Analysis at 4 to 6 weeks)
`“/c of Patients Cured [95% Confidence Interval]
`-1
`PRILOSEC +
`Clarithroinycin
`
`
`
`
`
`Sflfdy'1’26
`Study 127
`Study M96-446
`
`mean AUUM was
`ministered with oi
`
` greater. Claritli
`
`and mucus wer
`tion of omepraz
`Clarithromycin
`Tissue
`Antrum
`Fuiidus
`Mucus
`
`10
`20
`4
`
`1 Mean 1 SD (1
`For mforniatio:
`microbiology, c
`CLINICAL PH.
`The pliarinacol
`anioxicillin l‘iflVi
`drugs are admi
`For inforinatioit
`biology, see tl‘.
`PHARMACOL(
`Pharmacodynai
`Mechanism of}
`Oineprazole be
`pounds, the sul
`zinticliolinergic
`that suppress g
`the H*/K‘“ ATPa
`the gastiic pari
`garded as the or
`oineprazole has
`mliiliitor, in the
`This effect is d
`basal and stinii
`ulus. Animal s
`ance from plasi
`tric mucosa for
`Antisecrctory A
`After oral admi
`feet of onieprai
`mum effect occi
`tion is about 50
`of inhibition la
`thus lasts far In
`short (less thai
`to prolonged bi.
`When the drug
`gradually, over
`zole on acid se
`dosing, reacliin
`Results from m
`multiple doses 1
`volunteers and
`represents det
`(2—6 hours afii
`hours after the
`Range 0
`of the Me:
`
`Parameter
`Cb Decrease in
`Basal Acid Out
`% Decrease in
`Peak Acid Out}
`% Decrease in
`24-hr. Intragas
`Acidity
`
`* Single Studiei
`
`Single daily or:
`10 mg to 40 mi
`intragastric aci
`Entcmchromafl
`In 24-niontli ca
`significant moi-4
`liyperplasia we
`(see PRECAUT
`pairment of Fe.
`served in rats :
`niont with othe
`receptor antagc
`Human gastric
`more than 300‘
`term clinical tri
`these studies it
`cell C£|1‘C'ln0l(lS,
`these patients.
`Pzitliological H;
`Serum Gastrm
`In studies invoi
`levels inci 085581
`
`15% greater when ciarithroniycin was adi " F 7
`neprazole than when claritliromycin was
`I
`
`fifiilvxxlilli
`
`.§.;4§%-E’
`_
`iizlflli ,
`,
`
`rornycin concentrations 'ii’i'the gastr
`s also increased by concomitant administra-'
`ole.
`Tissue Concentrations 2 hours after Dose‘
`Clarithromycin + ‘
`Omeprazole
`
`Clarithromycin
`.48 t 2.01 (Ii = 5)
`.81 5; 7.64 in = 5)
`.15 i 7.74 (ii = 4)
`
`19 96 -_~ 4710; = 5)
`24 25 1 6.37 (n = 5)
`3929 : 3279(n=4)
`
`is/g)
`n on clarithromycin pharmacokinetics and
`onsiilt the clarithromycin package insert,
`XRMACOLOGY section
`nnetics of omeprazole, clarithromycin, and
`3 not been adequately studied when all three
`nistered concomitantly.
`l on anioxicillin pharinacokinetics and micro-
`e amoxicillin package insert, ACTIONS,
`)GY and MICROBIOLOGY sections.
`'m’cs
`lotion
`longs to a new class of antisecretory com-
`istitutcd henzimidazoles, that do not exhibit
`or 1-12 histamine antagonistic properties, but
`‘astric acid secretion by specific inhibition of
`se enzyme system at the secretory surface of
`etal cell Because this enzyme system is re-
`:id (proton) pump within the gastric mucosa,
`: been characterized as a gastric acid-pump
`it it blocks the final step of acid production.
`ose-ielated and loads to inhibition of both
`ilatcd acid secretion irrespective of the stiin-
`tudies indicate that after rapid disappear-
`na, onieprazole can be found within the gas-
`a day or more,
`ctiuzty
`nistration, the onset of the antisecretory ef-
`.ole occurs within one hour, with the maxi-
`1l'1'1ng within two hours. Inhibition of secre-
`% of maximum at 24 liouis and the duration
`sts up to 72 hours The antisecretory effect
`inger than would be expected from the very
`i one hour) plasma lialfilife, apparently due
`riding to the parietal H‘/K‘ ATPase enzyme.
`: is discontinued, secretory activity returns
`3 to 5 days. The inhibitory effect of omepra-
`cretion increases with repeated once-daily
`g a plateau after four days
`.
`inierous studies of the antisecretory effect of
`of 20 mg and 40 mg of omeprazole in normal
`patients are shown below. The “max” value
`erminations at a time of maximum efl"ect
`er dosing), while “min” values are those 24
`last dose of omeprazole.
`f Mean Values from Multiple Studies
`in Antisecretory Effects of Omeprazole
`gr Multiple Daily Dosing
`Omeprazole
`20 mg
`14%
`78*
`
`Omeprazole
`fling
`Mn
`80-93
`
`94*
`
`ME
`58-80
`
`put
`
`nut
`
`trio
`
`79*
`
`50-59
`
`88‘
`
`62-68
`
`80-97
`
`92-94
`
`i l
`
`PRILOSEC
`
`Claritlii oiiiycin
`
`U.S. Studies
`Study M93-067
`
`Study M93400
`Non U.S. Studies
`Study M92-812b
`
`Study M93-058
`
`0 [0, ‘ll
`74 [G0, 85] ii
`(n = 54)
`in = 53)
`0 [0, 61
`()4 [51, 76] it
`(n = 59)
`(Ii = 61)
`1 [0, 7]
`83 [71, 9215;
`(n = 74)
`(ii = 60)
`1 [0, 6]
`74 [64, 83}?
`(ii = 90)
`(ii = 86)
`lStatistically significantly higher than clarithroinycin nionot crapy (p < 0 05)
`$Statistically significantly higher than oniepiazole monotheiapy (p < 0.05)
`
`31 [18, 47]
`(n = 42)
`39 I24. 55]
`(I1 = 114)
`N/A
`
`N/A
`
`administration of therapeutic doses of omeprazole in paral-
`lel with inhibition of acid secretion. No further increase in
`serum gastrin occurred with continued treatment In com-
`paiison with histamine H2-receptor antagonists, the nie-
`dian increases produced by 20 mg doses of omeprazole were
`higher (1 3 to 3 6 fold vs 1.1 to 1 8 fold increase). Gastrin
`values returned to pretreatment levels, usually within 1 to
`2 weeks after discontinuation of therapy.
`Other E/feels
`Systemic effects of omepiazole in the CNS, cadiovascular
`and respiratory systems have not been found to date. Ome-
`prazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks,
`had no eliect on thyroid function, carbohydrate metabolism,
`or circulating levels of parathyioid hormone, cortisol, estra-
`diol, testosterone, prolactin, cholecystokinin or secretin.
`No effect on gastric emptying of the solid and liquid compo-
`nents ofa test meal was demonstrated after a single dose of
`omeprazole 90 mg In healthy subjects, a single I V,_ dose of
`omeprazole (0 35 mg/kg) had no effect on intrinsic factor se-
`cretion No systemic dose-dependent etiect has been ob-
`served on basal or stimulated pepsin‘ output in humans.
`However, when intragastric pH is maintained at 4.0 or
`above, basal pepsin output is low, and pepsin activity is de-
`creased.
`As do other agents that elevate intragaatric pH, omeprazole
`administered for 14 days in healthy subjects produced a sig-
`nificant increase in the intragastric concentrations of viable
`bacteria The pattern of the bacterial species was un-
`changed from that commonly found in saliva. All changes
`resolved within three days of stopping treatment.
`Clinical Studies
`Duodenal Ulcer Disease
`Active Duodenal Ulcer--In a multicenter, double-blind, pla-
`cebo-controlled study of 147 patients with endoscopically
`documented duodenal ulcer,
`the percentage of patients
`healed (per protocol) at 2 and 4 weeks was significantly
`higher with PRILOSEC 20 mg once a day than with placebo
`(13 S 0.01).
`
`Treatment ofActive Duodenal Ulcer
`% of Patients Healed
`PRILOSEC
`20 mg a.m
`.£n_.=..92>_
`‘41
`‘75
`
`Placebo
`a.m.
`.9: = 48>
`13
`27
`
`Week 2
`Week 4
`‘(p::0.01)
`
`‘Treatment of Active Duodenal Ulcer
`"’o of Patients Healed'
`PRILOSEC
`20 mg am.
`_(n = 145)
`42
`*82
`
`Ranitidine
`150 mg b i d
`in =. 148)
`34
`63
`
`i
`Week 2
`Week 4
`*(p<() ()1)
`Healing occurred significantly faster in patients treated
`with PRILOSEC than in those treated with ranitidine
`150 mg b.i.d, (p < 0.01).
`In a foreign multinational randomized, double-blind study
`of 105 patients with endoscopically documented duodenal
`ulcer, 20 mg and 40 mg of PRILOSEC were compared to
`150 mg b.i.d. of ranitidine at 2, 4 and 8 weeks. At 2 and
`4 weeks both doses ofPRILOSEC were statistically superior
`(per protocol) to ranitidine, but 40 mg was not superior to
`20 mg of PRILOSEC, and at 8 weeks there was no signifi-
`cant difference between any of the active dings.
`Treatment of Active Duodenal Ulcer
`% of Patients Healed
`PRILOSEC
`Ranitidine
`20 mg
`40 mg
`150 mg b.i d
`gn = 34)
`Q_§_3_6_)
`(I1 = 35)
`‘
`"83
`‘83
`53
`*9’?
`*100
`82
`100
`100
`94
`
`Week 2
`Week 4
`Week 8
`*(p.<.0.01)
`H pylon Eradication in Patients with Duodenal Ulcer
`Disease
`Triple Therapy (PRILOSEC/clarzthromycm/amoticillm)—-
`Tlii ee U.S., randomized, double-blind clinical studies in pa-
`tients with H pylori iiifection and duodenal ulcer disease
`(n = 558) compared PRILOSEC plus clzirithroiiiycin plus
`amoxicillin to claiithromyciri plus anioxicillin. Two studies
`(126 and 127) were conducted in patients with an active du-
`odenal ulcer, and the other study (M96446) was conducted
`in patients with a history of a duodenal ulcer in the past
`5 years but without an ulcer present at the tune of enroll-
`ment. The dose regimen in the studies was PRILOSEC
`20 mg b i (1. plus clarithiomycin 500 mg b.i.d plus amoxicil-
`lin 1 g b.i.d for 10 days, or clarithromycin 500 mg b.i.d plus
`anioxicillin 1 g b.i.d. for 10 days. In studies 126 and 127,
`patients who took the omeprazole regimen also received an
`additional 18 days of PRILOSEC 20 mg q.d Endpoints
`studied were eiadication of H pylori and duodenal ulcer
`healing (studies 126 and 127 only) H. pylori status was de-
`termined by CLOtest®, histology and culture in all three
`studies. For a given patient, H. pylori was considered crad-
`icated if at least two of these tests were negative, and none
`was positive.
`The combination of omeprazole plus clarithromycin plus
`ainoxicillin was cilective in eradicating H pylori
`[See first table at top of page}
`Dual Therapy (PRILOSEC/cltnit/itoniyciii)~—Four random-
`ized, doiible-bliiid, multi-center studies (I\l9B~067, M93-
`100, iVl9Z-8l2b, and M93—058) evaluated PRILOSEC 40 mg
`q d plus claiilhroinycin 500 mg t.i d. for 14 days, followed
`
`l doses of oiiieprazole ranging from a dose of
`; have produced 100% inhibition of 24-hour
`dity in some patients
`in-like (ECL) Cell Efiects
`rcinogenicity studies in rats, a dose-related
`iase in gastric carcinoid tumors and ECL cell
`s observed in both male and female animals
`[‘IONS, Carcinogenesis, Mutagenesis, lin-
`itility) Carcinoid tumors have also been ob-
`iubiected to fundectomy or long-term treat-
`r proton pump inhibitors or high doses of H2-
`vnists.
`Complete daytime and nighttime pain relicfoccurred signif-
`icantly faster (p S. 0.01) in patients treated with PRILOSEC
`biopsy specimens have been obtained from
`20 mg than in patients treated with placebo At the end of
`3 patients treated with omoprazole in long-
`the study, sigiiificantly more patients who had received
`als The incidence ofECL cell hyperplasio in
`icreased with time, however, no case of ECL
`PRILOSEC had complete relief of daytime pain (p S 0 05)
`and nighttime pain (p S 0.01).
`dysplasia, or ncoplasia has been found in
`(See also CLINICAL PHARMACOLOGY,
`In a multicenter, double-blind study of 293 patients with en-
`Ipersecretory Conditions )
`doscopically docunieiitcd duodenal ulcer, the percentage of
`E/fécts
`patients healed (per protocol) at 4 weeks was significantly
`higher with PRILOSEC 20 mg once a day than with multi-
`lving more than 200 patients, scrum gasti‘in
`dine 150 mg 13 1 d (p < 0 01)
`i during the first 1 to 2 weeks of oncc~daily
`.. . ......4.4 L,
`. a _q_-...... -...i .. .i...,.....,.,.i ...::.:,.....
`
`
`
`

`
`PRODUCT INFORMATION
`
`by PRILOSEC 20 mg q d. (M93—067, M93—-100, M93—058) or
`by PRILOSEC 40 mg q.d. (M92~812b) for an additional
`14 days in patients with active duodenal ulcer associated
`with H pylori Studies M93—067 and M93400 were con-
`ducted in the U.S and Canada and enrolled 242 and
`256 patients, respectively. H. pylori infection and duodenal
`ulcer were confirmed in 219‘patients in Study M93—067 and
`228 patients in Study M93—100. These studies compared
`the combination regimen to PRILOSEC and clarithromycin
`monotherapies. Studies M92—812b and M93—058 were con-
`ducted in Europe and enrolled 154 and 215 patients, respec-
`tively. H. pylori infection and duodenal ulcer were confirmed
`in 148 patients in study M92—812b and 208 patients in
`Study M93458. These studies compared the combination
`regimen to omeprazole monotherapy. The results for the ef-
`ficacy analyses for these studies are described below. H. py-
`lori eradication was defined as no positive test (culture or
`histology) at 4 weeks following the end of treatment, and
`two negative tests were required to be considered eradi-
`cated ofH pylon. In the per~protocol analysis, the following
`patients were excluded‘ dropouts, patients with missing H.
`pylori tests post-treatment, and patients that were not as-
`sessed for H. pylori eradication because they were found to
`have an ulcer at the end of treatment
`The combination of omeprazole and clarithromycin was
`elfective in eradicating H. pylori‘.
`[See second table at top of previous page]
`Ulcer healing was not significantly different when clarithro~
`mycin was added to omeprazole therapy compared to ome-
`prazole therapy alone.
`The combination of omeprazole and clarithromycin was ef-
`fective in eradicating H. pylori and reduced duodenal ulcer
`recurrence.
`
`Duodenal Ulcer Recurrence Rates by H. pylori Eradication
`Status, ‘in of Patients with Ulcer Recurrence
`
`H. pylori
`eradicated#
`
`H pylori
`not ei'adicatcd#
`
`U.S. Studiesi
`6 months post-treatm
`Study M93-067
`Study M93-100
`Non U S. Studiesi
`§ months post-treatment
`Study M92-812b
`_
`Study M93—058
`
`1_2ln_o_n_tl_i§ post-treatment
`Study M92-812b
`
`‘35
`(I1 = 49)
`*8
`(ii = 53)
`
`*5
`(n = 43)
`*6
`(n = 53)
`
`I5
`(n = 39)
`
`,
`
`60
`(11 5 38)
`60
`(ii = 106)
`
`46
`(n = 78)
`43
`(ii : 107)
`
`68
`(n = 71)
`
`#H. pylon eradication status assessed at same timepoint as
`ulcer recurrence
`i Combined results for PRILOSEC + clairthroniycin,
`PRILOSEC, and clarithromycin tieatment arms
`iCombined results for PRILOSEC + clarithromycin and
`PRILOSEC treatment arms
`“(p S 0.01) versus proportion with duodenal ulcer recur-
`rence who were not H. pylori eradicated
`Gastric Ulcer
`In a U S. multicenter, double-blind, study of omeprazole
`40 mg once a day, 20 mg once a day, and placebo in 520 pa-
`tients with endoscopically diagnosed gastric ulcer, the fol-
`lowing results were obtained.
`Treatment of Gastric Ulcer
`% of Patients Healed
`(All Patients Treated)
`PRILOSEC
`PRILOSEC
`Placebo
`20 mg q.d.
`40 mg q cl
`Ln = 104)_
`(n = 202)
`(n = 214)_
`30.8
`47.5**
`55.6“
`Week 4
`48.1
`74.8“
`82.7****
`Week 8
`**(p < 0.01) PRILOSEC 40 mg or 20 mg versus placebo
`"(p < 0.05) PRILOSEC 40 mg versus 20 mg
`For the stratified groups ofpatients with ulcer size less than
`or equal to 1 cm, no difference in healing rates between
`40 mg and 20 mg was detected at either 4 or 8 weeks For
`patients with ulcer size greater than 1 cm, 40 mg was sig-
`nificantly more eifcctive than 20 ing at 8 weeks.
`In a foreign, multinational, double—hlmd study of 602 pa-
`tients with endoscopically diagnosed gastric ulcer, omepra-
`zole 40 mg once a day, 20 mg once a day, and ranitidine
`150 mg twice a day were evaluated.
`Treatment of Gastric Ulcer
`% of Patients Healed
`(All Patients ’I\‘eated)
`PRILOSEC
`PRILOSEC
`20 mg q.d.
`40 mg q.d.
`I!]_=__2QQ)_
`(ii = 187)
`63.5
`78.1**’”
`Week 4
`81.5
`91 4**'”'
`Week 8
`“‘(p < 0.01) PRILOSEC 40 mg versus ranitidine
`“ (p < 0 01) PRILOSEC 40 mg versus 20 mg
`Gastrocsophageal Reflux Disease (GERD)
`Symptomatic GERD
`A placebo controlled study was conducted in Scandinavia to
`compare the eflicacy of omepramle 20 mg or 10 mg once
`
`Ranitidine
`150 mg b.i.d.
`(ii = 1191
`56.3
`78.4
`
`ASTRAZENECA LP/619
`
`Clarithroinycin Susceptibility Test Results and Clinical/Bacteriological Outcomes“
`Clarithiomycin
`«
`Clarithromycin Post-treatment Results
`Pretreatment Results
`1
`.
`
`H. pylon I
`negative-eradicated
`
`H. pylori positive-not eradicated
`
`sh
`
`R
`.
`Post-treatment susceptibility results
`1°
`
`No MIC
`
`Dual Therapy - (omeprazole 40 mg q.d./claritlironiycin 500 mg t.i.d. for 14 days followed by omeprazole 20 mg (id. for
`another 14 days) (Studies M93-O67, M93400)
` Susceptible“ 108 72
`
`Interinediate”
`1
`
`
`
`4
`
`Resistant”
`
`Triple Therapy - (omeprazole 20 mg b i.d./clarithromycin 500 mg ).i.d /amoxicillin 1 g b.i.d. for 10 days — Studies 126,
`127, M96-446; followed by omeprazole 20 mg q d. for another 18 days - Studies 126, 127)
`
`Slisceptlbleb
`Intermediate"
`
`171 I
`~4-
`
`153
`
`7
`
`l
`
`3 .
`
`6
`l
`i
`4
`14 L
`Resistant!’
`“Includes only patients with pretreatment clarithromycin susceptibility test results
`l’ Susceptible (S) MIC S 0.25 pg/mL, Intermediate (I) MIC 0.5-1.0 pg/mL, Resistant (R) MIC 2 2 iig/mL
`
`
`
`8
`
`3
`
`All patients
`
`daily for up to 4 weeks in the treatment of heartbum and
`other symptoms in GERD patients without erosive esopha-
`gitis Results are shown below.
`% Successful Symptomatic Outcome“
`PRILOSEC
`PRILOSEC
`20 mg a.n_L
`_19_ii1g_a_ip;
`46‘>'l‘
`31%
`(I! = 205)
`(ti = 199)
`56*”?
`361
`Patients with
`(D = 115)
`(I1 = 109)
`Confirmed
`GERD
`“Defined as complete resolution of heartburn
`*(p < 0.005) versus 10 mg
`‘i‘(p < 0 005) versus placebo
`Eraswe Esophagftis
`In a US. multicenter double-blind placebo controll